Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study

Abstract

IntroductionChronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as “at risk” for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE.MethodsOver the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE.ResultsWe will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology.ConclusionsThe UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.

Pathologically Confirmed Chronic Traumatic Encephalopathy in a 25-Year-Old Former College Football Player

“…Studies of clinicopathological correlation, such as the UNITE Study, 2 should help identify clinical features that are sensitive and specific for CTE pathology. Prospective studies that include neuropsychological testing with imaging and fluid biomarkers will be essential to future improvements in diagnosis of CTE during life.…”

“…1 Presently, CTE only can be diagnosed pathologically; however, research efforts, such as the ongoing Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) Study, 2 are investigating ways to diagnose CTE during life. As part of the UNITE Study, a panel of clinicians, blinded to neuropathology, make retrospective clinical consensus diagnoses using published criteria, including proposed clinical research criteria for CTE.…”

A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome

“…2 This study proposes analyzing the brains and spinal cords of 300 deceased individuals with a history of repetitive head trauma during the next 4 years. The investigators will use consensus neuropathologic data for diagnosis of CTE and an adaptation of the criteria of Montenigro et al 1,27 to perform a retrospective study of the clinical features of those individuals who meet minimum head trauma exposure criteria and the consensus neuropathologic criteria of CTE.…”

“…Although the term traumatic encephalopathy syndrome (TES) has been described previously when referring to the clinical syndrome associated with exposure to repetitive traumatic impact to the head (hereinafter referred to as head trauma), 1,2 it has been applied in a very general sense, used to refer to a wide variety of clinical outcomes after brain trauma. The construct of TES, however, should be very carefully and precisely elucidated.…”

“…Recently, the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study 2 was proposed to investigate the clinicopathologic correlation in patients with CTE findings and will analyze the brains and spinal cords of 300 deceased individuals during the next 4 years. Using clinical criteria based on those proposed by Montenigro et al 1 and consensus neuropathologic criteria, this group will retrospectively correlate pathologic findings with clinical features 2 to provide insight into their association. In contrast to the UNITE study, our proposed criteria are clinically based and can be applied prospectively and provide a framework to guide clinical diagnosis.…”